Diabetes therapy is increasingly based on a normal glycemic considerations. This normoglycemic orientation requires a determination of the individual glycemic conditions under everyday conditions to control, and in a given case correct, nutrition adjustments and bodily activity for therapeutic purposes. Even today in excess of 50% of diabetics die from later damage which results from insufficiently stable normal glycemic metabolic conditions. Avoidance of such late damages, and where possible a remission to reach damage that has already taken place can be achieved only through a thorough lowering of glucose values in blood, to realize a stable normal glycemic condition.
Since the criteria for this adjustment are different for various individuals, and are influenced by the aforementioned factors, often the control by a physician of variations in the blood sugar value within a 24 hour day represents a significant consideration for the therapy and for the avoidance of latent effects.
Depending on the type of diabetic, small daily profiles with 5-6 determinations throughout the day, or large daily profiles with 11 determinations over a 24 hour period, for 1 to 12 week periods, are considered important.
Until now, this medical requirement in a limited manner can be
1. satisfied by saving of self-taken blood samples and by subsequent enzymatic laboratory analysis; or
2. the diabetic tests his blood sugar content with a special test strip developed for that purpose, which provides a semi-quantitative, visual, or respectively by using a reflection measuring apparatus for a quantitative determination.
According to method 1, the diabetic must pick up the blood sample with a capillary, and each capillary is a small tube containing a preservative liquid. An industrial testing tool set is prepared which is then to be sent to a laboratory where preparation and analysis are carried out. The preserved blood samples can be held for about 10 days. The method is demanding and is expensive and can be employed only in a limited manner.
A reflectometric evaluation is carried out with method 2, makes a quantitative method available, that has a sufficient accuracy. A documentation of the results is, nevertheless, not available, because the instability of the coloration. This deficiency compels immediate evaluation by the diabetic himself and requires the acquisition or ready availability of measuring apparatus for the evaluation of the testing strip.
Due to the limited number of blood sugar analytical methods, aside from the pregnant, juvenile or labile diabetics, which are between 5 and 11 blood sugar determinations per month, or respectively, per quarter, the conduct of the determinations are further burdened by a spread in the individual results due to a lack routine techniques. Therefore, the physician cannot arrive at estimates and the judgment of the values is made more difficult. The material requirements under these circumstances can be satisfied only in the case of juvenile or pregnant diabetics.
For the above reasons, a testing by the diabetics themselves by daily determinations and evaluation by a physician is considered to be an optimal method. In this manner it is possible to develop a blood sugar profile control for all diabetics under medical evaluation and control.
Recognizing the problems of the color instability of known test strips, developments were created to eliminate this deficiency by means of simple or multi-layer film carrier membranes that are prepared in various ways with gelatins, enzymes, indicators and additives. Even though color stability can be accomplished in this manner, there are considerable shortcomings with respect to adaptability to reflection measuring instruments, due to indicator function or the absorption spectrum. In addition, the reaction capability is strongly influenced by humidity, heat and light and this has prevented the use of these materials to date.
The layering of film carrier membranes that are known per se, with enzyme-indicator gelatins by adding wetting agents, softeners, color couplers and curing agents, shows a high spread in quatitative determination of blood sugar values, i.e. insufficient precision, which is conditioned through washing out effect of the indicator system, variations in haematocrit content variable subsequent hardening of the layer, through storage influences and variations in water uptake, i.e. swelling.
In the case of practical application, it is mainly the question to match the absorption spectrum and the indicator function to the available measuring instruments to obtain the required stability for its use.
It is known to treat enzyme-indicator gelatin layers subsequently with aequous solutions of chromium-III salts. By means of this post-treatment the wet strength should increase, in that the degree of wetting of the gelatins is changed. This post-treatment only changes the surface characteristics and has n effect on the functionality, the absorption spectrum and the stability.
Enzyme-indicator gelatin layers are also known for glucose determina,tion in which biphenyl derivatives are employed as chromogen with a fixing material, in which a reaction at a pH &lt;5.0 results in a formation of a semiquinoneimine dye which will not wash out. Fixing and stability can be guaranteed absolutely only if when the liquid to be tested is not changed by this pH range, which, however, follows in the case of blood and sera having a pH around 7.0 and a action period effect of &gt;30 seconds. For this reason the precision is sufficient only in aqueous acid solutions and the extinction values obtained, cannot be compared with blood and sera.
It is also known to apply two enzyme-indicator gelatine layers containing different enzyme concentrations, for the improvement of the functionality. As already explained above, also here when the fixing material is applied for stabilization at pH &lt;5.0, the drawbacks of high spread, influence of haematocrits, and stability, are present without change.
The methods, test strips and layered membranes, respectively, all have the drawback that they cannot be adjusted to the reflection measuring apparati which are available in the trade for the last 10 years. The test strips that are now available are suitable only in a limited fashion for the determination of glucose daily profiles.